Fig. 1: Whole-genome sequencing of longitudinal FL/DHL samples reveals transformation-specific genomic alterations.
a, Eight cases of DHL with an available preceding FL sample diagnosed in the previous 17 years were identified. All DHL fulfilled WHO diagnostic criteria66, showing large B cell lymphoma morphology and harboring both MYC and BCL2 translocations identified in fluorescence in situ hybridization studies. For all patients, the FL sample preceded the DHL sample by months to years (average time to transformation 59 months, range 6–161 months). For one patient (P8), two FL samples were available in addition to the subsequent DHL. b, Schematic describing the BCL2 and MYC rearrangements observed for each patient. From WGS data, we identified all rearrangement breakpoints in the BCL2 and MYC loci. On the BCL2 locus, all tumor samples were found to harbor translocations to IGH, with breakpoints clustered in the 3′ UTR and downstream of BCL2. MYC rearrangements were mainly observed as DHL tumor-specific, with the exception of P4, which harbored an MYC translocation in both the FL and DHL samples. All three patients harboring MYC-IGH translocations (blue font) show breakpoints close to the first intron of the MYC gene. c, Mapping of BCL2-IGH and MYC-IGH translocations, and aSHM at BCL2, MYC and corresponding IGH loci. The occurrence of aSHM on BCL2 and MYC was significantly associated with IGH as the translocation partner (two-sided Fisher’s exact test P = 1.27 × 10−6). d,e, Plots showing increasing AF for BCL2 (d) and MYC (e) structural variants with transformation from FL to DHL (n = 8 patients). The MYC translocation in P4 was detected in both FL and DHL. P values were calculated by one-sided Wilcoxon signed-rank tests. The boxplots display 25th and 75th percentiles and the median of each group. Whiskers represent the highest and lowest values within 1.5× interquartile range. f, Comparison of mutational burden of FL compared to DHL in relation to the TSS, normalized and averaged over the cohort. A substantial concentration of mutations was observed within a 1,000 bp proximity of the TSS particularly within DHL. Only samples for which a nontumor DNA sequence was available are included in this analysis. AF, allele frequency.
